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                              October 20, 2020

       Meenu Chhabra
       Chief Executive Officer
       Proteostasis Therapeutics, Inc.
       80 Guest Street, Suite 500
       Boston, Massachusetts 02135

                                                        Re: Proteostasis
Therapeutics, Inc.
                                                            Registration
Statement on Form S-4
                                                            Filed September 23,
2020
                                                            File No. 333-248993

       Dear Ms. Chhabra:

              We have reviewed your registration statement and have the
following comments. In
       some of our comments, we may ask you to provide us with information so
we may better
       understand your disclosure.

              Please respond to this letter by amending your registration
statement and providing the
       requested information. If you do not believe our comments apply to your
facts and
       circumstances or do not believe an amendment is appropriate, please tell
us why in your
       response.

              After reviewing any amendment to your registration statement and
the information you
       provide in response to these comments, we may have additional comments.

       Form S-4 filed on September 23, 2020

       Questions and Answers About the Merger, page 1

   1.                                                   Please expand your
disclosure to discuss why the company is considering disposing of the
                                                        CF Assets. In this
discussion, please also disclose any factors that may be considered
                                                        when determining when
and whether to dispose of the CF Assets.
       Prospectus Summary, page 14

   2.                                                   We note that on page
15, 187, 192 and 231 that you state that "preliminary results suggest
                                                        that YTX-7739 is
generally safe and well tolerated." Please revise your document to
                                                        remove all statements
that indicate or imply that Yumanity's product candidates are safe
                                                        (or effective),
including preliminary indications of safety. Statements indicating safety are
                                                        premature because these
determinations are assessed by applicable regulators during all
 Meenu Chhabra
FirstName
ProteostasisLastNameMeenu
             Therapeutics, Inc.Chhabra
Comapany
October 20,NameProteostasis
             2020              Therapeutics, Inc.
October
Page 2 20, 2020 Page 2
FirstName LastName
         phases of clinical trials and Yumanity has not secured marketing
approval.
3.       We note that on page 44 you state there is an indication that
substantial doubt exists
         related to the ability of Yumanity to continue as a going concern.
Please expand your
         disclosure in your Prospectus Summary to include this information.
4.       Please disclose in your Prospectus Summary that none of Yumanity's
product candidates
         have advanced into late-stage development or a pivotal clinical study.
Please also disclose
         that the combined company will need substantial additional funding to
continue to
         advance its products through clinical trials. We note your disclosures
on pages 46 and 47
         in this regard.
Reasons for the Merger, page 17

5.       Disclose in more detail "the risks and challenges of attempting to
continue to operate
         Proteostasis on a stand-alone basis." For example, discuss any
financial challenges or
         other challenges in advancing product candidates.
Opinion of Proteostasis    Financial Advisor, page 18

6.       Please state here, if true, that your financial advisor ascribed no
value to the CF Assets in
         preparing its fairness opinion and that your advisor assumed that your
only material asset
         was your cash.
Background fo the Merger, page 105

7.       Expand your disclosure to discuss how the parties arrived at the key
terms of the merger
         agreement, including the exchange ratio.
8.       We note that you disclose that Yumanity's historical operating results
indicate a
         substantial doubt exists related to its ability to continue as a going
concern. Please expand
         your disclosure here to discuss how the company considered Yumanity's
financial
         condition when evaluating the merger.
9.       Discuss in more detail the negotiations over the terms of the CVR
agreement. In this
         discussion, disclose how the parties reached the final terms,
including the declining
         proceeds CVR Holders receive with the passage of time.
Proteostasis Valuation Analysis, page 123

10.      In light of the CVR Agreement and the potential value that may be
derived from the CF
         Assets, please revise to clarify why you believed it was appropriate
to direct MTS to
         assume that your only material asset was cash, including if you
considered whether any
         value could or should be attributed to the CF Assets for purposes of
the fairness
         opinion. If there is some value associated with the CF Assets, please
include a risk factor
         that discusses the risks of this assumption and the potential effects
it may have had on the
         analysis.
 Meenu Chhabra
FirstName
ProteostasisLastNameMeenu
             Therapeutics, Inc.Chhabra
Comapany
October 20,NameProteostasis
             2020              Therapeutics, Inc.
October
Page 3 20, 2020 Page 3
FirstName LastName
Discounted Cash Flow Analysis, page 124

11.      We note the disclosure that at the direction of Proteostasis, MTS
conducted sensitivity
         analyses in connection with the discounted cash flow analysis using
regulatory
         probabilities of success during Phase I and during Phase II. Please
clarify whether the
         analysis included the regulatory probability of success for Phase III
and the probability of
         success for regulatory approval that are indicated on page 130 or
revise your disclosure as
         appropriate.
Yumanity's Pipeline, page 191

12.      Please expand your pipeline charts on pages 192 and 200 to include all
clinical stages that
         must be completed before commercialization of Yumanity's product
candidates (i.e., add
         columns for phases 2 and 3).
13.      We note your disclosure in the third paragraph following the table on
page 192 that, with
         respect to YTX-7739, Yumanity plans to initiate a Phase 2 trial in
patients in 2021. Please
         revise your disclosure so that it reconciles to the information
presented in your table
         which indicates Phase 2 initiation in 2022.
Collaboration Agreement with Merck, page 208

14.      We note your disclosure that under the Merck Collaboration Agreement,
Yumanity is
         eligible to receive up to $530 million upon achievement of certain
milestones. Please
         revise your disclosure to separately disclose the amounts receivable
in research,
         development and sales milestones. Please also revise the description
of the tiered
         royalties Yumanity is eligible to receive to disclose a percentage
range for those royalties
         of no more than ten percentage points, and revise to clarify when the
royalty obligations
         would end.
Unaudited Pro Forma Condensed Combined Financial Information, page 275

15.      We note that you are accounting for the transaction between
Proteostasis and Yummanity
         as a reverse acquisition and asset acquisition under ASC 805. Please
tell us how you
         considered the guidance in ASC 805-40-25-1 which states that for a
business combination
         transaction to be accounted for as a reverse acquisition, the
accounting acquiree must meet
         the definition of a business.
16.      Notwithstanding the above comment, please provide us a full analysis
of ASU 2017-01
         and ASC 805-10-55-4 through 55-6 and 805-10-55-8 through 55-9 in
determining
         that Proteostasis is not a business in order to support your
conclusion that the merger
         should be accounted for as an asset acquisition. For example, the
guidance states that
         although businesses usually have outputs, outputs are not required for
an integrated set to
         qualify as a business, for example, an early stage company that has
not generated
         revenues.
 Meenu Chhabra
Proteostasis Therapeutics, Inc.
October 20, 2020
Page 4

        We remind you that the company and its management are responsible for
the accuracy
and adequacy of their disclosures, notwithstanding any review, comments, action
or absence of
action by the staff.

       Refer to Rules 460 and 461 regarding requests for acceleration. Please
allow adequate
time for us to review any amendment prior to the requested effective date of
the registration
statement.

        You may contact Kristin Lochhead at (202) 551-3664 or Daniel Gordon at
(202) 551-
3486 if you have questions regarding comments on the financial statements and
related
matters. Please contact Courtney Lindsay at (202) 551-7237 or Tim Buchmiller at
(202) 551-
3635 with any other questions.



                                                           Sincerely,
FirstName LastNameMeenu Chhabra
                                                           Division of
Corporation Finance
Comapany NameProteostasis Therapeutics, Inc.
                                                           Office of Life
Sciences
October 20, 2020 Page 4
cc:       Courtney T. Thorne, Esq.
FirstName LastName