Does Huntingtin play a role in selective macroautophagy?

Figures & data

Figure 1 Htt may have evolved from Cvt proteins Atg23, Vac8 and Atg11. (A) The yeast Vac8 protein contains 11 armadillo repeats which can be described as ancestral HEAT repeats. Throughout evolution, Vac8 may have fused with yeast protein Atg23 on the amino-terminus and Atg11 on the C-terminus. These yeast proteins are essential for the cytoplasm to vacuole targeting (Cvt) selective autophagic pathway, which is activated by TORC1 in yeast grown under nutrient-rich conditions. The cartoon is not drawn to scale. (B) A protein complex essential for the yeast Cvt pathway may be similar to a hypothetical human complex required for selective macroautophagy under nutrient-rich conditions.

Figure 2 Model: The kinase IKK may activate Htt degradation by a mammalian version of the yeast Cvt pathway. The kinase IKK, activated by inflammatory stimuli, insulin signaling, DNA damage and oxidative stress pathways,48,118–120,153,154 Rheb155 and by PINK/parkin,146,147 phosphorylates Htt S13 and activates Htt acetylation by CBP/p300 and caspase cleavage,13 targeting the amino-terminal fragments of Htt for degradation by the proteasome and lysosome.1 IKK reduces interaction of Bcl-x_L/Bcl-2 with Beclin-1,4,13,148 thereby priming activation of both starvation-induced and the proposed mammalian Cvt macroautophagic pathways. IKK activates JNK1 and CBP/p300 to increase levels of p62/SQSTM1,4,8,43,148,149 required for the Cvt pathway and AMPK4 which may then activate starvation-induced macroautophagy as a compensatory feedback mechanism. Mutant Htt expression activates IKK.2 The proposed mammalian Cvt pathway, activated by CBP/p300 or inhibition of Sirt1 by nicotinamide, may be involved in vesicle-mediated degradation of phosphorylated/acetylated Htt N-terminal fragments by the lysosome. With aging and mutant Htt expression, the proteasome and this Cvt-like mechanism of autophagy may become impaired, and this loss of function may be compensated for by activation of starvation/rapamycin/AMPK/Sirt1-induced macroautophagy.

Table 1 Yeast Cvt pathway proteins and their hypothetical human functional homologs

Yeast protein	Function	Interactors	Human protein	Function	Interactors
Atg1	Kinase required for vesicle and PAS formation	Atg1, Atg8, Atg11, Atg13, Atg14, Atg17, Atg18, Atg21, Atg29, Slx5	ULK1/2	Kinase that regulates autophagy156	mAtg13
Atg8	Vesicle component, phagophore expansion, vesicle fusion	Atg1, Atg3, Atg4, Atg7, Atg19, Atg32, Vam3	LC3	Recruited to the phagophore membrane and remains associated with completed vesicle102	p62/SQSTM1
Atg11	Directs receptor-bound cargo to the PAS for packaging into vesicles; required for recruiting other proteins to the PAS	Atg1, Atg9, Atg11, Atg12, Atg17, Atg19, Atg20, Atg29, Atg32	Huntingtin aa 1743–3144	Regulation of early endosome motility89	HAP40/Rab5 complex
			FIP200	Regulation of cell growth, proliferation, cell migration, apoptosis, microtubule dynamics, stress response156,157	mAtg13, ULK1/2, PIASy, p53, FAK, TSC1, Pyk2, ASK1 stathmin, TRAF2
Atg13	Regulatory subunit of Atg1 complex, required for vesicle formation, involved in Atg9/23/27 cycling	Vac8, Atg1, Atg17	mAtg13	Plays an essential role in autophagosome formation, phosphorylated by ULK and mTOR156,158	ULK1/2, FIP200, Atg101
Atg17	Scaffold protein responsible for PAS site organization, stimulates Atg1 kinase activity	Atg1, Atg9, Atg11, Atg12, Atg13, Atg17, Atg24, Atg29, NIP100	Atg101	Important for stability and phosphorylation of ULK and mAtg13158	mAtg13
Atg19	Cvt pathway receptor protein delivers cargo to PAS	Atg8, Atg11, Ubi4	p62/SQSTM1 NBR1	Shuttle proteins transport ubiquitinated proteins to lysosome54,55,93,102,159	LC3, Huntingtin, ubiquitin
Atg20	Sorting nexin for Cvt pathway and endosomal sorting	Atg11, Atg24	Optineurin	Membrane trafficking, cellular morphogenesis59	Huntingtin, Rab8
Atg23	Peripheral membrane protein required for Atg9/Atg27 shuttling/membrane trafficking	Atg9, Atg27	Huntingtin aa 1–586	Contains polyQ repeat, vesicle/membrane trafficking, localizes to microtubules59,77,85,160	HAP-1, Optineurin, p53, Sp1, Akt, CBP, SH3GL3, RasGaP, PSD-95, HIP-1, HYP-J, PACSIN, actin
Atg24	Sorting nexin involved in Cvt pathway and in retrieval of late-Golgi SNAREs from post-Golgi endosomes to the trans-Golgi network	Atg17, Atg20, Cog6, NIP100	HAP-1	Adaptor protein, mediates vesicle trafficking62,161	Huntingtin (171–230) PCM-1, kinesin-like protein, neurofilament M, p150^glued
Vac8	Vacuole inheritance, the Cvt pathway, mitophagy, PMN, vacuole/vacuole fusion	Atg13, Vam3, Act1	Huntingtin aa 807–1653	DNA-damage response signal protein45	Cdk5
Vam3	Integral vacuolar membrane protein required for vacuolar assembly and protein trafficking, Golgi to vacuole transport, vesicular fusion, PMN	Atg8, Vac8, Vam3, Vam7	LAMP-2A	Integral lysosomal membrane protein involved in vesicular trafficking and lysosome biogenesis70,150,162	UCH-L1/Hsc70/Hsp90 complex
NIP100	Large subunit of dynactin complex	Atg24	p150^glued	Large subunit of dynactin complex62	HAP-1

Select direct interactions listed. Yeast protein data obtained from the Saccharomyces Genome Database: www.yeastgenome.org.

Dan HC, Cooper MJ, Cogswell PC, Duncan JA, Ting JP, Baldwin AS. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 2008; 22:1490 - 1500

 PubMed Web of Science ®Google Scholar

Hayden MS, Ghosh S. Signaling to NFkappaB. Genes Dev 2004; 18:2195 - 2224

 PubMed Web of Science ®Google Scholar

Wu ZH, Shi Y, Tibbetts RS, Miyamoto S. Molecular linkage between the kinase ATM and NFkappaB signaling in response to genotoxic stimuli. Science 2006; 311:1141 - 1146

 PubMed Web of Science ®Google Scholar

Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009; 122:3589 - 3594

 PubMed Web of Science ®Google Scholar

Hasegawa M, Fujimoto Y, Lucas PC, Nakano H, Fukase K, Nunez G, et al. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NFkappaB activation. EMBO J 2008; 27:373 - 383

 PubMed Web of Science ®Google Scholar

Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412:179 - 190

 PubMed Web of Science ®Google Scholar

Sha D, Chin LS, Li L. Phosphorylation of parkin by Parkinson disease-linked kinase PINK1 activates parkin E3 ligase function and NFkappaB signaling. Hum Mol Genet 2010; 19:352 - 363

 PubMed Web of Science ®Google Scholar

Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, Kim J, et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 2010; 107:378 - 383

 PubMed Web of Science ®Google Scholar

Khoshnan A, Ko J, Tescu S, Brundin P, Patterson PH. IKKalpha and IKKbeta regulation of DNA damage-induced cleavage of huntingtin. PLoS One 2009; 45768

 Google Scholar

Thompson LM, Aiken CT, Kaltenbach LS, Agrawal N, Illes K, Khoshnan A, et al. IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome. J Cell Biol 2009; 187:1083 - 1099

 PubMed Web of Science ®Google Scholar

Criollo A, Senovilla L, Authier H, Maiuri MC, Morselli E, Vitale I, et al. The IKK complex contributes to the induction of autophagy. EMBO J 2010; 29:619 - 631

 PubMed Web of Science ®Google Scholar

Puissant A, Robert G, Fenouille N, Luciano F, Cassuto JP, Raynaud S, et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation. Cancer Res 2010; 70:1042 - 1052

 PubMed Web of Science ®Google Scholar

Huang WC,, Ju TK, Hung MC, Chen CC. Phosphorylation of CBP by IKKalpha promotes cell growth by switching the binding preference of CBP from p53 to NFkappaB. Mol Cell 2007; 26:75 - 87

 PubMed Web of Science ®Google Scholar

Lee IH, Finkel T. Regulation of autophagy by the p300 acetyltransferase.. J Biol Chem 2009; 284:6322 - 6328

 PubMed Web of Science ®Google Scholar

Verma UN, Yamamoto Y, Prajapati S, Gaynor RB. Nuclear role of IkappaB Kinase-gamma/NFkappa B essential modulator (IKKgamma/NEMO) in NFkappaB-dependent gene expression. J Biol Chem 2004; 279:3509 - 3515

 PubMed Web of Science ®Google Scholar

Khoshnan A, Ko J, Watkin EE, Paige LA, Reinhart PH, Patterson PH. Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity. J Neurosci 2004; 24:7999 - 8008

 PubMed Web of Science ®Google Scholar

Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett 2010; 584:1287 - 1295

 PubMed Web of Science ®Google Scholar

Komatsu M, Ichimura Y. Physiological significance of selective degradation of p62 by autophagy. FEBS Lett 2010; 584:1374 - 1378

 PubMed Web of Science ®Google Scholar

Pal A, Severin F, Lommer B, Shevchenko A, Zerial M. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is upregulated in Huntington's disease. J Cell Biol 2006; 172:605 - 618

 PubMed Web of Science ®Google Scholar

Hara T, Mizushima N. Role of ULK-FIP200 complex in mammalian autophagy: FIP200, a counterpart of yeast Atg17?. Autophagy 2009; 5:85 - 87

 PubMed Web of Science ®Google Scholar

Hosokawa N, Sasaki T, Iemura S, Natsume T, Hara T, Mizushima N. Atg101, a novel mammalian autophagy protein interacting with Atg13. Autophagy 2009; 5:973 - 979

 PubMed Web of Science ®Google Scholar

Chang CY, Huang WP. Atg19 mediates a dual interaction cargo sorting mechanism in selective autophagy. Mol Biol Cell 2007; 18:919 - 929

 PubMed Web of Science ®Google Scholar

Lynch-Day MA, Klionsky DJ. The Cvt pathway as a model for selective autophagy. FEBS Lett 2010; 584:1359 - 1366

 PubMed Web of Science ®Google Scholar

Bjorkoy G, Lamark T, Brech A, Outzen H, Perander M, Overvatn A, et al. p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 2005; 171:603 - 614

 PubMed Web of Science ®Google Scholar

Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol 2007; 9:1102 - 1109

 PubMed Web of Science ®Google Scholar

Hattula K, Peranen J. FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and modulates cellular morphogenesis. Curr Biol 2000; 10:1603 - 1606

 PubMed Web of Science ®Google Scholar

Colin E, Zala D, Liot G, Rangone H, Borrell-Pages M, Li XJ, et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J 2008; 27:2124 - 2134

 PubMed Web of Science ®Google Scholar

Angeli S, Shao J, Diamond MI. F-actin binding regions on the androgen receptor and huntingtin increase aggregation and alter aggregate characteristics. PLoS One 2010; 5:9053

 Web of Science ®Google Scholar

Harjes P, Wanker EE. The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 2003; 28:425 - 433

 PubMed Web of Science ®Google Scholar

Engelender S, Sharp AH, Colomer V, Tokito MK, Lanahan A, Worley P, et al. Huntingtin-associated protein 1 (HAP1) interacts with the p150Glued subunit of dynactin. Hum Mol Genet 1997; 6:2205 - 2212

 PubMed Web of Science ®Google Scholar

Bertaux F, Sharp AH, Ross CA, Lehrach H, Bates GP, Wanker E. HAP1-huntingtin interactions do not contribute to the molecular pathology in Huntington's disease transgenic mice. FEBS Lett 1998; 426:229 - 232

 PubMed Web of Science ®Google Scholar

Anne SL, Saudou F, Humbert S. Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J Neurosci 2007; 27:7318 - 7328

 PubMed Web of Science ®Google Scholar

Saftig P, Beertsen W, Eskelinen EL. LAMP-2: a control step for phagosome and autophagosome maturation. Autophagy 2008; 4:510 - 512

 PubMed Web of Science ®Google Scholar

Koga H, Kaushik S, Cuervo AM. Altered lipid content inhibits autophagic vesicular fusion. FASEB J 2010; 24:3052 - 3065

 PubMed Web of Science ®Google Scholar

Kabuta T, Furuta A, Aoki S, Furuta K, Wada K. Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J Biol Chem 2008; 283:23731 - 23738

 PubMed Web of Science ®Google Scholar